A Family of Drug Transporters: the Multidrug Resistance-Associated Proteins

Abstract

The human multidrug resistance-associated protein (MRP) family currently has seven members. The ability of several of these membrane proteins to transport a wide range of anticancer drugs out of cells and their presence in many tumors make them prime suspects in unexplained cases of drug resistance, although proof that they contribute to clinical drug resistance is still lacking. Recent studies have begun to clarify the function of the MRP family members. MRPs are organic anion transporters; i.e., they transport anionic drugs, exemplified by methotrexate, and neutral drugs conjugated to acidic ligands, such as glutathione (GSH), glucuronate, or sulfate. However, MRP1, MRP2, and MRP3 can also cause resistance to neutral organic drugs that are not known to be conjugated to acidic ligands by transporting these drugs together with free GSH. MRP1 can even confer resistance to arsenite and MRP2 to cisplatin, again probably by transporting these compounds in complexes with GSH. MRP4 overexpression is associated with high-level resistance to the nucleoside analogues 9-(2-phosphonylmethoxyethyl) adenine and azidothymidine, both of which are used as anti-human immunodeficiency virus drugs. MRPs may, therefore, also have a role in resistance against nucleoside analogues used in cancer chemotherapy. Mice without Mrp1, a high-affinity leukotriene C(4) transporter, have an altered response to inflammatory stimuli but are otherwise healthy and fertile. MRP2 is the major transporter responsible for the secretion of bilirubin glucuronides into bile, and humans without MRP2 develop a mild liver disease known as the Dubin-Johnson syndrome. The physiologic functions of the other MRPs are not known. Whether long-term inhibition of MRPs in humans can be tolerated (assuming that suitable inhibitors will be found) remains to be determined.

Both P-gp and MRP2 mediate transport of Lopinavir, a protease inhibitor

“…These proteins transport substrates against a concentration gradient with ATP hydrolysis as a driving force across the membrane. P-gp, a multiple drug resistant (MDR) gene product, transports a wide range of compounds, including anticancer drugs, steroids, calcium channel blockers and antihistamines (Endicott and Ling, 1989;Borst et al, 1993;Germann et al, 1993;Borst et al, 2000;Pal and Mitra, 2006). P-gp-mediated efflux reduces the intracellular accumulation of these compounds, thereby diminishing drug efficacy.…”

Resolution of P‐glycoprotein and non‐P‐glycoprotein effects on drug permeability using intestinal tissues from mdr1a (−/−) mice

“…Relatively little is known about the transport characteristics of LRP and BCRP. MRP type transporters, studied primarily in over-expressing cell models, have the capacity to transport many substances including common drugs, often following enzymatic conjugation with glutathione, glucuronide or sulphate, although some MRPs may also act as unconjugated drug/glutathione co-transpor-ters Borst et al, 2000). Several members of the MRP family have been identi®ed at the molecular level in intestinal tissues (Mottino et al, 2000;Peng et al, 1999;Gotoh et al, 2000) and there is evidence that at least one of these, MRP2, is functionally active in this tissue (Gotoh et al, 2000).…”

The role of bioreductive activation of doxorubicin in cytotoxic activity against leukaemia HL60-sensitive cell line and its multidrug-resistant sublines

“…However, their clinical usefulness is limited by the occurrence of multidrug resistance (MDR) associated with the presence of membrane transporters (e.g. P-glycoprotein, MRP1), belonging to the ATP-binding cassette protein family (Gottesman and Pastan, 1993;Germann, 1996;Marie et al, 1996;Borst et al, 2000). These transporters are responsible for the active ATP-dependent efflux of drugs out of resistant cells resulting in the decreased intracellular accumulation insufficient to inhibit resistant cell proliferation (Zaman et al, 1994;Paul et al, 1996).…”